Antiallergics are compounds which prevent, inhibit or alleviate allergic reactions. It is believed that these compounds characteristically function as cell stabilizers and/or mast cell inhibitors preventing the usual degranulation of the mast cells in response to the presence of allergens. The eye, particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present, they can bind to the immunoglobulin on the surface of these mast cells and trigger the breakdown, or what is known as the degranulation, of the cell. On degranulation, mast cell components, including histamines, are released into the environment outside the mast cell. Through a variety of mechanisms, these components can be responsible for symptoms associated with allergic responses such as itching, redness, lid swelling, vasodilation and chemosis.
Disodium cromoglycate (DSCG) has been used as an antiallergic to treat allergic conditions such as: vernal or allergic and chronic conjunctivitis (Acta Ophthalmologica, Vol.58, pp.121-124, 1980); vernal keratoconjunctivitis (Current Eye Research, Vol.2, No.11, 1982-83); and giant papillary conjunctivitis (Arch. Ophthalmol.-Vol.100, pp.1608-1610, 1982). DSCG has been reported as irritating to some patients (Arch. Ophthalmol., Vol.100, No. 1, pp.412-413, 1982).
Cyano phenylene dioxamic compounds disclosed generally in U.S. Pat. No. 3,993,679 issued to Hall et al., and specifically for use as topical ophthalmic antiallergenics in U.S. patent application Ser. No. 312,434, both of which are incorporated herein by reference, are also antiallergic compounds useful in preventing allergic reactions resulting in mast cell degranulation. A species of the defined cyano phenylene dioxamic compounds of particular interest and representative thereof is N-N'-(2-chloro-5-cyano-m-phenylene)dioxamic acid and its pharmaceutically acceptable salts and esters, such as di-[tris (hydroxymethyl)methylammonium]-N-N'(2-chloro-5-cyano-m-phenylene)dioxamate also known as lodoxamide tromethamine, the active referred to herein as lodoxamide. Although the antiallergic, lodoxamide, is known to be efficacious in the treatment of allergic responses when topically applied to the eye, it can cause eye irritation and systemic side effects; see Watt et al., J. Allergy Clin. Immunology, Vol. 66, No.4 (1980).
Antihistamines are compounds which are administered to prevent histamines, released from mast cells in response to the presence of allergens, from binding to, for example, nerves and smooth muscle cells of the conjunctival blood vessels causing redness, itching and swelling. They serve to prevent or alleviate many of the symptoms which can result from degranulation of mast cells.
A combination of 4% DSCG and 0.2% of the antihistamine, chlorpheniramine maleate (Visuglican) has been used in patients with different forms of allergic conjunctivitis; see, Bonini et al., Studies of Allergic Conjunctivitis, Chibret Int'l J. of Ophth., Vol.5, No.2, 1987.
It is an object of the present invention to provide improved ophthalmic compositions comprising an antiallergic and an antihistamine, for treating existing symptoms of mast cell degranulation caused by the release of histamines and preventing further allergic and inflammatory symptoms by stabilizing the mast cells of the eye, or by inhibitng the allergic reaction which results in mast cell degranulation and ocular irritation.
It is a further object to provide methods for preventing and treating ophthalmic allergic conditions through administration of the disclosed compositions.